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"Karsinoma payudara (KPD) merupakan kanker terbanyak pada perempuan dan lebih dari 90% kematian akibat kanker diebabkan oleh adanya metastasis. Diperlukan terapi yang tidak hanya fokus pada proliferasi, tetapi juga fokus pada proses metastasis. Jalur Rho/ROCK diketahui memengaruhi invasi dan metastasis. Studi terbaru menunjukkan bahwa jalur Rho/ROCK berperan penting pada regulasi migrasi dan proliferasi sel, sehingga dapat dijadikan target terapi. Selain mereduksi biosintesis kolesterol melalui inhibisi 3-hydroxy-3-methylglutaryl coenzyme A reductase, statin juga mengurangi formasi isoprenoid intermediates yang diperlukan untuk mediasi pensinyalan melalui jalur Rho/ROCK. Statin diduga dapat menghambat jalur Rho/ROCK dan aman digunakan dalam jangka panjang. Penelitian ini bertujuan untuk mengetahui efek antimetastasis (migrasi dan proliferasi) simvastatin terhadap KPD melalui jalur Rho/ROCK. Penelitian ini merupakan uji intervensi perioperative "window", parallel unmatching, randomized, double-blinded, dan placebo-controlled yang berlangsung sejak November 2014 hingga Juli 2015. Sebanyak 30 pasien KPD diberikan terapi simvastatin 40 mg/hari dan plasebo selama 4-6 minggu lalu dilakukan mastektomi di RSCM, RSPAD Gatot Subroto, RS Persahabatan, dan RSUD Koja. Perubahan migrasi (indeks migrasi, aktivitas ROCK dan kadar mRNA RhoC, CXCR4, dan CD44) dan reduksi proliferasi (ekspresi Ki67) yang didapat dari jaringan biopsi dan mastektomi dievaluasi sebelum dan sesudah terapi. Kemudian karakteristik yang berbeda bermakna dianalisis juga hubungannya dengan kadar kolesterol darah, grade, status ER/PR, dan status HER-2. Simvastatin 40 mg/harimenurunkan indeks migrasi (p=0,006), aktivitas ROCK (p=0,002), kadar mRNA CXCR4 (p=0,045) dan ekspresi Ki67 (p<0,001) secara bermakna. Terdapat tren penurunan kadar mRNA RhoC (p=0,163) dan CD44 (p=0,094). Penurunan aktivitas ROCK berhubungan dengan kolesterol tinggi (p=0,008), grade rendah (p=0,019) dan amplifikasi HER- 2 (p=0,009). Penurunan kadar mRNA CXCR4 berhubungan dengan kolesterol tinggi (p=0,024), ER/PR positif (p=0,013), dan amplifikasi HER-2 (p=0,018). Penurunan ekspresi Ki67 berhubungan dengan kolesterol tinggi (p=0,001), grade rendah (p=0,017) dan tinggi (p=0,018), HER-2 (p=0,002) dan negatif (p=0,034), serta ER/PR positif (p=0,007) dan negatif (p=0,042). Simvastatin dapat menginhibisi migrasi dan menyupresi proliferasi pada KPD melalui jalur Rho/ROCK, sehingga dapat digunakan sebagai terapi pencegahan metastasis kanker payudara.

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Breast cancer is the most common cancer among women and more than 90% of cancer deaths are caused by metastasis. There is an urgent need for the development of therapeutic intervention specifically targeted to the metastatic process. The Rho/ROCK pathway is found to be involved in invasion and metastasis. Recent studies have revealed that the Rho/ROCK pathway plays a critical role in regulation of cancer cell migration and proliferation, making it a potential therapy target. Besides reducing cholesterol biosynthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins also decrease the formation of isoprenoids intermediates essential for mediating the Rho/ROCK signalling. Statin is thought to inhibit the Rho/ROCK pathway and is safe for long-term use.

This study aimed to determine the antimetastasis (migration and proliferation) effect of simvastatin on breast cancer through the Rho/ROCK pathway. In a parallel unmatching, randomized, double-blinded, placebo-controlled, perioperative "window" interventional trial conducted from November 2014 until July 2015, 30 breast cancer subjects were treated with simvastatin 40 mg/day or placebo for 4-6 weeks followed by mastectomy (n=15 in each arm) at Cipto Mangunkusumo Hospital, Gatot Subroto Army Hospital, Persahabatan Hospital and Koja Hospital. Changes in migration (migration index, ROCK activity, mRNA RhoC, CXCR4 and CD44 level) and proliferation (Ki67 expression) from biopsy and final surgical specimen were obtained before and after intervention. The relationships of significant factors with blood cholesterol level, grade, ER/PR and HER-2 status were analyzed.

Simvastatin 40 mg/d significantly reduced migration index (p = 0.006), ROCK activity (p = 0.002), mRNA CXCR4 level (p = 0.045) and reduced Ki67 expression (p < 0.001). Decreased was also observed for mRNA RhoC (p = 0.163) and CD44 level (p = 0.094). Reduced ROCK activity was related to high cholesterol level (p = 0.008), low grade (p = 0.019) and HER-2 amplification (p = 0.009). Reduced CXCR4 transcription was related to high cholesterol level (p = 0.024), positive ER/PR (p = 0.013) and HER-2 amplification (p = 0.018). Ki67 expression was related to high cholesterol level (p = 0.001), low (p = 0.017) and high grade (p= 0.018), with (p = 0.002) and without HER-2 amplification (p = 0.034), and positive (p = 0.007) and negative (p = 0.042) ER/PR status. Simvastatin inhibits the migration and proliferation in breast cancer through Rho/ROCK pathway, hence holds a promising potential as prophylaxis for breast cancer metastasis."

"Human oral tongue cancer (SP-C1) is thought to be a high grade malignancy. Despite advances in surgery, radiotherapy, chemotherapy and combination therapy, prognosis and survival of patients with human tongue cancer have not significantly improved over the past several decades. Treatment options for recurrent or refractory tongue cancer are limited. Therefore, as a strategy for refractory cancer, anti-mitotic chemotherapy and its mechanisms are of considerable interest, including those using docetaxel hydrate for inducing maspin protein. In the current study, the mechanisms responsible for growth suppression and metastasis of SP-C1 by docetaxel hydrate through induction of maspin regulation were investigated. To evaluate in vitro cell proliferation and cell metastasis, MTT and out-growth assays were performed, respectively. Furthermore, the expression of maspin mediated by docetaxel hydrate was analysed by Western blotting. The results showed that treatment with 50 g/ml docetaxel hydrate significantly suppressed SP-C1 cell growth from day 1. Strong inhibition of metastasis of SP-C1 cells was also shown by treatment with 50 g/ml of docetaxel hydrate. Moreover, a significant induction of maspin regulation was detected in cells treated with 10 and 50 g/ml of docetaxel hydrate. However, the same protein level wasdemonstrated in -tubulin expression. These findings suggest thatdocetaxel hydrate may have potential for powerful anti-mitoticchemotherapy through induction of maspin regulation."

"Latar Belakang: Penurunan sensitivitas hingga resistensi terhadap tamoksifen sering terjadi dalam pengobatan kanker payudara jangka panjang. Salah satu penyebab utamanya adalah peningkatan ekspresi transporter efluks P-glikoprotein (P-gp) dan Breast Cancer Resistance Protein (BCRP). Kurkumin diketahui sebagai penghambat P-gp dan BCRP. Pemberian kurkumin pada sel yang telah menurun sensitivitasnya terhadap tamoksifen diharapkan mampu meningkatkan sensitivitas sel kanker payudara terhadap tamoksifen melalui penghambatan kedua transporter tersebut. Metode: Sel MCF-7 dipaparkan tamoksifen 1 µM selama 10 pasasi (sel MCF-7(T)), kemudian dianalisis perubahan sensitivitas sel terhadap tamoksifen melalui viabilitas sel dan ekspresi mRNA P-gp dan BCRP. Pada sel MCF-7(T), kurkumin diberikan dalam dosis 5, 10, dan 20 µM dengan atau tanpa tamoksifen selama 5 hari dan dianalisis viabilitas sel dan ekspresi mRNA P-gp dan BCRP pada hari ke-2 dan 5. Sebagai kontrol positif, verapamil 50 µM digunakan sebagai penghambat P-gp, ritonavir 15 µM dan nelfinavir 15 µM sebagai penghambat BCRP. Hasil: Setelah diberikan tamoksifen 1 µM selama 10 pasasi (44 hari), sel MCF-7(T) menurun sensitivitasnya terhadap tamoksifen yang dibuktikan dengan terjadinya pergeseran CC50 sebesar 32,08 kali, peningkatan viabilitas sel sebesar 106,4%, dan peningkatan ekspresi mRNA P-gp dan BCRP sebesar 10,82 kali dan 4,04 kali. Pemberian kurkumin dengan atau tanpa tamoksifen selama 5 hari dapat menurunkan viabilitas sel dan ekspresi mRNA P-gp dan BCRP (p < 0,05). Kesimpulan: Kurkumin meningkatkan sensitivitas sel MCF-7(T) terhadap tamoksifen yang ditandai dengan penurunan viabilitas sel dan ekspresi mRNA P-gp dan BCRP. Peningkatan sensitivitas tersebut diduga terjadi melalui penghambatan ekspresi mRNA P-gp dan BCRP oleh kurkumin.

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Background: Decrease of sensitivity or resistance to tamoxifen occurs after long-term treatment in breast cancer. One of the major factor in tamoxifen resistance is overexpression of efflux transporter P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Curcumin has been known as inhibitor of P-gp and BCRP. The addition of curcumin to tamoxifen resistant cells is expected to increase the sensitivity of breast cancer cells to tamoxifen.

Methods: MCF-7 breast cancer cell line was exposed with tamoxifen 1 µM for 10 passage (MCF-7(T)), then cell viability and mRNA expression of P-gp and BCRP were analyzed. To the MCF-7(T) cells, curcumin of 5, 10, dan 20 µM with or without tamoxifen was given for 5 days and cell viability and mRNA expression of P-gp and BCRP were analyzed on day 2 and 5. As positive control, verapamil 50 µM was used as P-gp inhibitor, ritonavir 15 µM and nelfinavir 15 µM were used as BCRP inhibitor.

Results: The administration of tamoxifen 1 µM for 10 passage (44 days), caused a decreased of MCF-7(T) cells sensitivity to the drug, with 32,08 times reduction in CC50 towards tamoxifen, increased of cell viability of 106,4%, and increased mRNA expression of P-gp and BCRP mRNA of 10,82 and 4,04 fold, respectively. The administration of curcumin with or without tamoxifen for 5 days reduced cell viability and the mRNA expression of P-gp mRNA and BCRP (p < 0,05).

Conclusion: Curcumin increased MCF-7(T) sensitivity to tamoxifen, characterized by decreased of cell viability and mRNA expression of P-gp and BCRP. Increased of sensitivity was estimated at least in part through inhibition of P-gp and BCRP mRNA expression by curcumin. "

"Latar Belakang: Sel punca kanker merupakan populasi sel minor yang memiliki kemampuan self-renewal dan proliferasi tak terbatas sehingga bersifat tumorigenik dan diduga berperan dalam penurunan sensitivitas terhadap berbagai terapi kanker. Tamoksifen merupakan terapi lini pertama pada kanker payudara ER positif namun penggunaan jangka panjangnya menimbulkan masalah resistensi. Beberapa faktor yang diduga berperan dalam penurunan sensitivitas sel terhadap Tamoksifen yakni modulasi pensinyalan estrogen melalui ERα66; dan ERα36 (yang diketahui memperantarai pensinyalan non-genomik), serta ekspresi transporter effluks seperti MRP2 yang berperan dalam penurunan kadar Tamoksifen intraseluler. Penelitian ini bertujuan untuk menganalisis efek pemaparan Tamoksifen berulang pada sel punca kanker payudara CD24-/CD44+, dalam kaitannya mengenai sensitivitas terapi melalui perubahan ekspresi estrogen reseptor alfa dan transporter efluks MRP2.Metode: Selpunca kanker payudara CD24-/CD44+ dipaparkan Tamoksifen 1 μM selama 21 hari dengan DMSO sebagai kontrol negatif. Viabilitas sel setelah pemaparan Tamoksifen diuji dengan metode trypan blue exclusion. Sifat tumorigenik sel setelah pemaparan (CD24-/CD44+(T)) diuji dengan mammossphere formation assay dan dibandingkan dengan sel CD24-/CD44+(0) yang belum dipaparkan Tamoksifen. Ekspresi mRNA Oct4, c-Myc, ERα66, ERα36 dan MRP2 dianalisis dengan one step quantitative RT-PCR.Hasil: Terjadi penurunan sensitivitas sel punca kanker payudara CD24-/CD44+(T) yang dipaparkan Tamoksifen selama 21 hari yang ditunjukkan dengan kenaikan viabilitas sel hingga 125,2%. Tamoksifen tidak dapat menekan sifat tumorigenik sel CD24-/CD44+(T) yang dibuktikan melalui jumlah mammosfer yang tidak berbeda bermakna dibandingkan dengan CD24-/CD44+(0). Penurunan sensitivitas sel CD24-/CD44+(T) juga dibuktikan melalui peningkatan ekspresi Oct4 dan c-Myc; keduanya merupakan petanda pluripotensi dan c-Myc juga dikenal sebagai petanda keganasan. Parameter penurunan sensitivitas seperti ERα66, ERα36 dan MRP2 juga menunjukkan peningkatan ekspresi pada hari ke-15 namun menurun kembali pada hari ke-21 yang menunjukkan adanya mekanisme regulasi lain yang mungkin terlibat dalam penurunan sensitivitas sel punca kanker payudara terhadap Tamoksifen.Kesimpulan: Pemaparan Tamoksifen berulang dapat menurunkan sensitivitas sel punca kanker payudara CD24-/CD44+ melalui perubahan ekspresi estrogen reseptor alfa dan transporter efluks MRP2.

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Background: Cancer stem cells are minor population of cells possessing self-renewal and unlimited proliferation abilities which support their tumorigenicity and role in decreased sensitivity to many cancer therapies. Tamoxifen is a first line therapy for breast cancer patients with positive ER status. Nonetheless, after 5 years of its long term use eventually leads to recurrence and resistance in 50% of patients receiving tamoxifen therapy. Among some factors that might play role in decreased sensitivity to tamoxifen are modulation of estrogen signaling through ERα66 and ERα36 (the latter known for its non-genomic estrogen signaling), and expression of efflux transporter such as MRP2 responsible for decreased intracellular tamoxifen level. The objective of this study is to analyze the effects of repeated tamoxifen exposure toward decreased sensitivity of the breast cancer stem cells CD24-/CD44+ through changes in expression of estrogen receptor alpha and efflux transporter MRP2.

Methods: Breast cancer stem cells CD24-/CD44+ were exposed to 1 μM tamoxifen for 21 days with DMSO as negative control. After exposure with 1 μM tamoxifen, the cell viability were tested by the trypan blue exclusion method. Cell tumorigenicity of tamoxifen-exposed CD24-/CD44+(T) and CD24-/CD44+(0) (before treatment) were tested by the mammosphere formation assay. The expression of Oct4, c-Myc, ERα66, ERα36 andMRP2 mRNAs were analyzed by one step quantiative RT-PCR.

Results: A decreased sensitivity of the breast cancer stem cells CD24-/CD44+ exposed with 1 μM tamoxifen for 21 days was observed as indicated by an increased cell viability up to 125.2%. In the presence of tamoxifen, breast cancer stem cells CD24-/CD44+(T) exhibited tumorigenic properties as indicated in no significant difference in the formation of mammosphere unit compared to those of CD24-/CD44+(0). After exposure with 1 μM tamoxifen for 21 days, an elevated level of Oct4 and c-Myc expressions were observed; both are known as pluripotency markers and the latter also known as marker of aggresiveness. Parameters for a decreased sensitivity such as ERα66, ERα36 and MRP2 also exhibited an elevated expression after 15 days of exposure, but the decreased expression after 21 days of exposure suggests that there might be another mechanism involved in decreased sensitivity of the breast cancer stem cells toward tamoxifen.

Conclusion: Repeated tamoxifen exposure may decrease the sensitivity of the breast cancer stem cells CD24-/CD44+ through changes in expression of estrogen receptor alpha and efflux transporter MRP2."

"Latar Belakang: Sel punca kanker merupakan populasi sel minor yang memiliki kemampuan self-renewal dan proliferasi tak terbatas sehingga bersifat tumorigenik dan diduga berperan dalam penurunan sensitivitas terhadap berbagai terapi kanker. Tamoksifen merupakan terapi lini pertama pada kanker payudara ER positif namun penggunaan jangka panjangnya menimbulkan masalah resistensi. Beberapa faktor yang diduga berperan dalam penurunan sensitivitas sel terhadap Tamoksifen yakni modulasi pensinyalan estrogen melalui ER?66; dan ER?36 (yang diketahui memperantarai pensinyalan non-genomik), serta ekspresi transporter effluks seperti MRP2 yang berperan dalam penurunan kadar Tamoksifen intraseluler. Penelitian ini bertujuan untuk menganalisis efek pemaparan Tamoksifen berulang pada sel punca kanker payudara CD24-/CD44+, dalam kaitannya mengenai sensitivitas terapi melalui perubahan ekspresi estrogen reseptor alfa dan transporter efluks MRP2.Metode: Selpunca kanker payudara CD24-/CD44+ dipaparkan Tamoksifen 1 ?M selama 21 hari dengan DMSO sebagai kontrol negatif. Viabilitas sel setelah pemaparan Tamoksifen diuji dengan metode trypan blue exclusion. Sifat tumorigenik sel setelah pemaparan (CD24-/CD44+(T)) diuji dengan mammossphere formation assay dan dibandingkan dengan sel CD24-/CD44+(0) yang belum dipaparkan Tamoksifen. Ekspresi mRNA Oct4, c-Myc, ER?66, ER?36 dan MRP2 dianalisis dengan one step quantitative RT-PCR.Hasil: Terjadi penurunan sensitivitas sel punca kanker payudara CD24-/CD44+(T) yang dipaparkan Tamoksifen selama 21 hari yang ditunjukkan dengan kenaikan viabilitas sel hingga 125,2%. Tamoksifen tidak dapat menekan sifat tumorigenik sel CD24-/CD44+(T) yang dibuktikan melalui jumlah mammosfer yang tidak berbeda bermakna dibandingkan dengan CD24-/CD44+(0). Penurunan sensitivitas sel CD24-/CD44+(T) juga dibuktikan melalui peningkatan ekspresi Oct4 dan c-Myc; keduanya merupakan petanda pluripotensi dan c-Myc juga dikenal sebagai petanda keganasan. Parameter penurunan sensitivitas seperti ER?66, ER?36 dan MRP2 juga menunjukkan peningkatan ekspresi pada hari ke-15 namun menurun kembali pada hari ke-21 yang menunjukkan adanya mekanisme regulasi lain yang mungkin terlibat dalam penurunan sensitivitas sel punca kanker payudara terhadap Tamoksifen.Kesimpulan: Pemaparan Tamoksifen berulang dapat menurunkan sensitivitas sel punca kanker payudara CD24-/CD44+ melalui perubahan ekspresi estrogen reseptor alfa dan transporter efluks MRP2.

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Background: Cancer stem cells are minor population of cells possessing self-renewal and unlimited proliferation abilities which support their tumorigenicity and role in decreased sensitivity to many cancer therapies. Tamoxifen is a first line therapy for breast cancer patients with positive ER status. Nonetheless, after 5 years of its long term use eventually leads to recurrence and resistance in 50% of patients receiving tamoxifen therapy. Among some factors that might play role in decreased sensitivity to tamoxifen are modulation of estrogen signaling through ER?66 and ER?36 (the latter known for its non-genomic estrogen signaling), and expression of efflux transporter such as MRP2 responsible for decreased intracellular tamoxifen level. The objective of this study is to analyze the effects of long term tamoxifen exposure toward decreased sensitivity of the breast cancer stem cells CD24-/CD44+ through changes in expression of estrogen receptor alpha and efflux transporter MRP2.

Methods: Breast cancer stem cells CD24-/CD44+ were exposed to 1 ?M tamoxifen for 21 days with DMSO as negative control. After exposure with 1 ?M tamoxifen, the cell viability were tested by the trypan blue exclusion method. Cell tumorigenicity of tamoxifen-exposed CD24-/CD44+(T) and CD24-/CD44+(0) (before treatment) were tested by the mammosphere formation assay. The expression of Oct4, c-Myc, ER?66, ER?36 andMRP2 mRNAs were analyzed by one step quantiative RT-PCR.

Results: A decreased sensitivity of the breast cancer stem cells CD24-/CD44+ exposed with 1 ?M tamoxifen for 21 days was observed as indicated by an increased cell viability up to 125.2%. In the presence of tamoxifen, breast cancer stem cells CD24-/CD44+(T) exhibited tumorigenic properties as indicated in no significant difference in the formation of mammosphere unit compared to those of CD24-/CD44+(0). After exposure with 1 ?M tamoxifen for 21 days, an elevated level of Oct4 and c-Myc expressions were observed; both are known as pluripotency markers and the latter also known as marker of aggresiveness. Parameters for a decreased sensitivity such as ER?66, ER?36 and MRP2 also exhibited an elevated expression after 15 days of exposure, but the decreased expression after 21 days of exposure suggests that there might be another mechanism involved in decreased sensitivity of the breast cancer stem cells toward tamoxifen.

Conclusion: Long term tamoxifen exposure may decrease the sensitivity of the breast cancer stem cells CD24-/CD44+ through changes in expression of estrogen receptor alpha and efflux transporter MRP2."

"Karakteristik sel punca kanker payudara sangat penting diketahui untuk memaksimalkan terapi kanker payudara. Interaksi antara sel punca dengan lingkungan mikronya merupakan salah satu karakter sel punca yang diteliti pada penelitian ini. Lingkungan mikro, misalnya sel fibroblas, dapat mempengaruhi proliferasi sel punca kanker payudara melalui suatu jalur persinyalan tertentu. Penelitian ini bertujuan untuk mengamati perbedaan proliferasi sel punca kanker payudara dengan beberapa perlakuan berbeda, yaitu berupa pengko-kulturan dengan sel fibroblas normal dan kanker, dengan menggunakan uji MTT dan MTS. Sel punca kanker payudara yang diko-kultur dengan sel fibroblas dipanen pada hari kedua dan keempat untuk diamati secara mikroskopik dan diuji proliferasinya. Pengamatan secara mikroskopik, menunjukkan bahwa sel punca kanker payudara yang diko-kultur dengan sel fibroblas kanker mengalami peningkatan jumlah mammospheres yang mengindikasikan sifat kepuncaan sel kanker. Pengujian MTT dan MTS memperoleh hasil yang serupa, yaitu lingkungan mikro, dalam hal ini berupa sel fibroblas, dapat mempengaruhi tingkat proliferasi sel punca kanker payudara. Sel punca kanker payudara yang diko-kultur dengan sel fibroblas kanker menunjukkan tingkat proliferasi yang lebih tinggi dibandingkan dengan yang diko-kultur dengan sel fibroblas normal.

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Understanding the characteritics of breast cancer stem cell is essential to optimize breast cancer therapy. The interaction between stem cell and microenvironment is one of these characteristics which is examined in this study. Fibroblast cell as an example of stem cell microenvirontment can influence breast cancer stem cell proliferation through some particular signaling pathways. The objective of the study is to observe the difference of breast cancer stem cell proliferation under some conditions, which are co-cultured with normal fibroblast cell and cancer fibroblast cell, to understand the interaction of stem cell and its microenvironment. Breast cancer stem cell co-cultured with fibroblast cell was harvested on second day and fourth day to be examined microscopically and to be tested by using proliferation assay, such as MTT and MTS assay. Microscopic examination showed that breast cancer stem cell co-cultured with cancer fibroblast cell exhibited an increase amount of mammospehere, which indicate a stem cell like properties. MTT and MTS assay showed similar results, that microenvironment can influence breast cancer stem cell proliferation. Breast cancer stem cell co-cultured with cancer fibroblast cell showed a higher proliferation level compared to the one co-cultured with normal fibroblast cell."

"Latar belakang: Terjadinya penurunan sensitivitas sel kanker terhadap doksorubisin merupakan masalah yang terjadi pada terapi metastatic breast cancer. Salah satu penyebab turunnya sensitivitas sel kanker payudara terhadap doksorubisin adalah overekspresi transporter efluks BCRP. Penambahan silimarin, suatu senyawa golongan flavonoid diketahui memiliki efek antikanker dan penghambat BCRP, diharapkan dapat meningkatkan kembali sensitivitas sel kanker terhadap doksorubisin. Metode: Doksorubisin dipaparkan pada sel sel kanker payudara, MCF-7 selama 14 hari, kemudian dianalisis perubahan sensitivitas sel terhadap doksorubisin dengan melihat persentase sel hidup dan ekspresi mRNA BCRP. Pada sel tersebut, silimarin diberikan dalam dosis 10/25/50/100 μM dengan atau tanpa doksorubisin 0,1 mM selama 7 hari dan dianalisis persentase sel hidup dan ekspresi mRNA BCRP pada hari ke-3 dan ke-7. Ritonavir 19 μM digunakan sebagai kontrol positif penghambat BCRP. Hasil: Pajanan doksorubisin 0,1 μM selama 14 hari, menurunkan sensitivitas sel MCF-7 terhadap doksorubisin (MCF-7/Dox) dibuktikan dengan terjadinya pergeseran CC50 sebesar 9,5 kali, peningkatan persentase sel hidup, dan ekspresi mRNA BCRP sebesar 9,7 kali. Silimarin berbagai konsentrasi yang dikombinasikan dengan doksorubisin 0,1 mM mampu menurunkan persentase sel hidup secara bermakna pada hari ke-3 dan ke-7 yang disertai dengan penurunan ekspresi mRNA BCRP. Silimarin tunggal yang diberikan tanpa doksorubisin, tidak mampu menurunkan persentase sel hidup walaupun terjadi penurunan ekspresi mRNA BCRP yang bermakna. Kesimpulan: Kombinasi doksorubisin dan silimarin dapat meningkatkan sensitivitas sel MCF-7 terhadap doksorubisin. Peningkatan sensitivitas tersebut terjadi melalui penghambatan ekspresi mRNA BCRP oleh silimarin. Kombinasi doksorubisin dengan silimarin diharapkan dapat menjadi kandidat obat sebagai cochemotherapy metastasis kanker payudara yang sudah mengalami penurunan sensitivitas."

"ABSTRAKLatar Belakang: Trombositosis pada pasien kanker payudara KPD diduga berkontribusi pada penyebaran dan sifat invasi sel punca kanker payudara. Modifikasi lingkungan mikro tumor dapat dilakukan untuk meningkatkan efektivitas terapi anti kanker. Belum diketahui apakah platelet derived growth factor PDGF -AB dalam lisat trombosit LT juga berperan terhadap cancer stem cell CSC payudara CD24-/CD44 .Tujuan: Penelitian ini bertujuan untuk menganalisis efek LT dan PDGF-AB didalamnya sebagai lingkungan mikro tumor pada proliferasi dan sifat invasi sel punca kanker payudara CD24-/CD44 yang ditandai dengan kadar matrix metalloproteinase-9 MMP-9 dan epithelial-cadherin E-cadherin . Metode: Penelitian ini merupakan studi eksperimental pada kultur sel punca KPD yang diberi LT dari pasien KPD dan donor sehat. Darah semua donor dilakukan pemeriksaan hematologi dan diproses untuk mendapatkan platelet rich plasma PRP . Jumlah trombosit per ?L PRP setiap donor dihitung. PRP diproses untuk mendapatkan LT. Kadar PDGF-AB LT diukur. LT 0,01 ditambahkan ke dalam medium dulbecco rsquo;s modified eagle rsquo;s medium DMEM -F12 untuk kultur sel punca KPD. Setelah inkubasi 48 jam, total jumlah sel, population doubling time PDT dan viabilitas sel dihitung dan dinormalisasikan terhadap nilai kontrolnya. Ekspresi MMP-9 dan E-cadherin dipilih sebagai penanda biologi sifat invasi dan diukur dengan metode enzyme-linked immunosorbent assay ELISA . Jumlah total sel, PDT, viabilitas sel, kadar MMP-9 dan E-cadherin dibandingkan antara pasien KPD dan donor sehat lalu dianalisis korelasinya dengan jumlah trombosit dan kadar PDGF-AB dalam lisat trombosit. Hasil: Jumlah trombosit dan kadar PDGF-AB dalam LT pasien KPD lebih tinggi dibandingkan LT donor sehat, keduanya dengan nilai p=0,02. LT pasien KPD memicu proliferasi sel punca KPD lebih baik dibandingkan LT donor sehat p

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ABSTRACTBackground Thrombocytosis in breast cancer BC patient is supposed to play a role in the invasiveness of breast cancer stem cells. Modification of tumor microenvironment was proposed to increase the efficacy of anticancer therapy. Aim This study aimed to analyze the effect of platelet lysate PL as well as its platelet derived growth factor PDGF AB content as a tumor microenvironment on the CD24 CD44 breast cancer stem cell BCSC proliferation and invasiveness. Methods This experimental study treated BCSC culture with PL from BC patients or healthy donors. Venous blood from all donors were subjected to hematology test and processed to obtain PRP. Platelet counts in PRP were determined. PRP was processed to obtain PL. PDGF AB contents in PL were measured. PL 0.01 was supplemented into dulbecco rsquo s modified eagle rsquo s medium DMEM F12 medium and used for culturing the CD24 CD44 BCSCs . After 48 hours, total cell count, population doubling time PDT , and cell viability were calculated and normalized to its control. Matrix metalloproteinase 9 MMP 9 and E cadherin was used as biological marker for CSC invasiveness and measured by enzyme linked immunosorbent assay ELISA method. Total cell count, PDT, cells viability as well as MMP 9 and E cadherin levels between BCSC, healthy donor platelet lysate and control group were compared and their correlation with platelet count in PRP and PDGF AB levels in platelet lysates were analyzed. Results Platelet counts and PDGF AB levels were higher in BC patient PL compared to healthy donor group, both with a p value of 0.02. BC patient PL could stimulate the proliferation of BCSCs higher than healthy donor PL p"

"Latar belakang: Kanker payudara merupakan kanker tersering dengan mortalitas kematian kelima tertinggi di dunia. Tamoksifen, terapi hormon lini pertama kanker payudara ditemukan kasus resisten pada sel kanker dengan ekspresi c-myc yang tinggi. C-myc adalah faktor transkripsi yang menginduksi proliferasi, diferensiasi, serta metastasis sel kanker. Penelitian terbaru telah menemukan lunasin, protein dari ekstrak kedelai yang dinilai memiliki berbagai efek antikanker. Tujuan penelitian ini adalah mengetahui apakah lunasin dapat menurunkan ekspresi protein c-myc pada sel kanker payudara. Metode: Desain penelitian adalah true-experimental laboratorium dengan sampel preparat jaringan kanker payudara tikus tersimpan. Kelompok sediaan terdiri kelompok normal, kontrol negatif, kontrol positif, terapi kombinasi (lunasin dan tamoksifen) dan lunasin. Jaringan diwarnai secara imunohistokimia dengan diaminobenzinidie (DAB) dan antibodi anti-c-myc. Sediaan dipotret dengan mikroskop cahaya perbesaran 400 kali sebanyak 5 lapang pandang secara acak. Hasil berupa H-score ekspresi c-myc yang dihitung menggunakan software ImageJ dengan plugin immunohistochemistry (IHC) Profiler. Hasil: Kelompok dengan indeks H-score tertinggi berurutan adalah kontrol negatif (174), terapi tamoksifen, (149,4), terapi lunasin (146,6), kombinasi (138,6), dan normal (129,4). Ekspresi c-myc pada seluruh kelompok berbeda signifikan dibandingkan dengan kontrol negatif. Perbandingan setiap dua kelompok juga berbeda signifikan kecuali antara kelompok kontrol positif dengan lunasin. Kesimpulan: Lunasin dari ekstrak kedelai menghambat ekspresi protein c-myc pada sel kanker payudara tikus yang diinduksi DMBA. Lunasin dan tamoksifen masing-masing mampu menurunkan ekspresi protein c-myc. Terapi kombinasi lunasin dan tamoksifen paling efektif menurunkan ekspresi c-myc sel kanker payudara

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Introduction: Breast cancer is the most prevalent and the fifth leading cause of death in the world. Tamoxifen, the first-line hormone therapy, which is found to be resistant to breast cancer cells with high c-myc expression. C-myc is a transcription factor that induces the proliferation, differentiation, and metastasis of cancer cells. Recent research has discovered lunasin, protein derived from soybean extract that have anticancer activities. The aim of this study was to determine whether lunasin can reduce c-myc protein expression in breast cancer. Method: The study design is a true-experimental laboratory with stored rat breast cancer tissue samples. The group was consisted of normal group, negative control, positive control, combination therapy (lunasin and tamoxifen) and lunasin. Tissues were stained with anti-c-myc adnd was photographed with a light microscope equipped with a 400x magnification camera with 5 fields of view at random. The result is an H-score of c-myc expression which is calculated using Image J software with the immunohistochemistry profiler plugin. Result: The groups with the highest H-score value to the lowest, respectively, are negative control (174), positive control (149,4), lunasin therapy (146,6), combination therapy (138,6), and normal (129,4). The C-myc expression in all groups is significantly different compared to the negative control. Conclusion: Lunasin inhibits the expression of c-myc protein in DMBA-induced rat breast cancer. Lunasin and tamoxifen are each able to reduce c-myc expression. The most effective way to reduce c-myc expression on breast cancer cells is combination therapy (lunasin and tamoxifen)."

"Latar Belakang: Kanker payudara merupakan kanker dengan insidensi tertinggi kedua di dunia pada tahun 2018. Setiap 100.000 wanita di Indonesia, 40 mengidap kanker payudara. Mortalitas pada kanker payudara paling banyak disebabkan oleh kejadian metastasis organ viseral yang dilaporkan memiliki prognosis lebih buruk dibandingkan metastasis non viseral. Ekspresi reseptor hormonal (HR) dan proteinHER2 atau subtipe intrinsik molekular diindikasikan dapat memprediksi jenis atau lokasi metastasis kanker payudara. Karena itu, perlu ada penelitian tentang hubungan HR dan HER2 terhadap jenis metastasis kanker payudara, terutama pada populasi di Indonesia untuk memperkirakan perjalanan penyakit.Tujuan: Mengetahui hubungan antara reseptor hormonal dan HER2 terhadap jenis metastasis kanker payudara, viseral maupun non viseral.Metode: Penelitian dengan desain cross sectional ini menggunakan data dari sembilan puluh satu pasien kanker payudara dengan metastasis yang dipilih dengan cara consecutive sampling dari RSCM dan RS MRCCC Siloam. Status HR dan HER2 diambil dari pemeriksaan imunohistokimia, sedangkan jenis metastasis diambil dari hasil pemeriksaan radiologi atau patologi anatomi. Data diolah denganuji chi square dan disajikan dalam bentuk tabel.Hasil: Analisis bivariat antara HR dengan metastasis viseral menghasilkan nilai OR 0,549 (95% CI 0,165-1,829), dengan metastasis non viseral OR 1,533 (95% CI 0,565-4,157), dan dengan kedua metastasis viseral dan non viseral OR 0,960 (95% CI 0,351-2,624). Untuk analisis antara protein HER2 dengan metastasis viseralmenghasilkan OR 2,333 (95% CI 0,825-6,599), dengan metastasis non viseral OR 0,538 (95% CI 0,223-1,302), dan dengan kedua metastasis viseral dan non viseral OR 1,061 (95% CI 0,442-2,549). Semua analisis menghasilkan p>0,05.Kesimpulan: Tidak ditemukan adanya hubungan yang bermakna antara HR maupun HER2 terhadap jenis metastasis kanker payudaraBackground: Breast cancer is a cancer with the second highest incidence in the world in 2018. For every 100,000 women in Indonesia, 40 suffer from breast cancer. Mortality in breast cancer is mostly caused by the incidence of visceral organ metastases which are reported to have a worse prognosis than non-visceral metastases. Hormonal receptor (HR) and protein expressionHER2 or molecular intrinsic subtypes are indicated to predict the type or location of breast cancer metastases. Therefore, there needs to be research on the relationship between HR and HER2 to the type of breast cancer metastases, especially in the population in Indonesia to estimate the course of the disease.Objective: To determine the relationship between hormonal receptors and HER2 on the type of breast cancer metastasis, visceral and non-visceral.Methods: This cross-sectional design study used data from ninety-one breast cancer patients with metastases selected by consecutive sampling from RSCM and MRCCC Siloam Hospital. HR and HER2 status were taken from immunohistochemical examination, while the type of metastasis was taken from the results of radiological examination or anatomical pathology. Data processed with chi square test and presented in tabular form.Results: Bivariate analysis of HR with visceral metastases resulted in OR 0.549 (95% CI 0.165-1.829), with non-visceral metastases OR 1.533 (95% CI 0.565-4.157), and with both visceral and non-visceral metastases OR 0.960 (95% CI 0.351-2.624). For analysis between HER2 protein and visceral metastases resulted in an OR of 2.333 (95% CI 0.825-6.599), with non-visceral metastases OR 0.538 (95% CI 0.223-1.302), and with both visceral and non-visceral metastases OR 1.061 (95% CI 0.442-2.549). All analyzes yielded p>0.05.Conclusion: There was no significant relationship between HR and HER2 on the type of breast cancer metastases"